Neoplasia, also known as cancer, is the second most common cause of death in the United States. While the survival rates for individuals with cancer have increased considerably in the last few decades, survival of the disease is far from assured. Cancer is a catch-all term for over 100 different diseases, each of which are each fundamentally characterized by the unchecked proliferation of cells. Individual cancer cells are also able to break off from the main tumor, or metastasize, creating additional tumors in other regions of the body.
Melanoma is a very serious form of cancer. Recently, the number of new melanomas diagnosed has been increasing. The American Cancer Society estimates that about 51,400 new melanomas will be diagnosed in the United States during 2001, and about 7,800 deaths will be attributed to the disease.
Melanoma is a malignant tumor of melanocytes. Although most melanomas arise in the skin, they also may arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than half of the cases arise in apparently normal areas of the skin. Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, tumor infiltrating lymphocytes, and ulceration or bleeding at the primary site affect the prognosis. Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.
Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis. The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion. Some melanomas that have spread to regional lymph nodes may be curable with wide excision of the primary tumor and removal of the involved regional lymph nodes. Adjuvant chemotherapy has not been shown to increase survival. Melanoma that has spread to distant sites is generally not curable with standard therapy, although long-term survival is occasionally achieved by resection of metastasis. Such patients are appropriately considered candidates for clinical trials exploring new forms of therapy.
Recently, immunotherapies by using melanoma-specific antigens or epitopes have been documented, with immunogenic antigens identified including human tyrosinase, TRP-1 (tyrosinase related protein 1), TRP-2, a group of enzymes involved in melanin biosynthetic pathway, MART-1/melan-A (Melanoma Antigen Recognized by cytolytic T cells-1), MAGE-1, BAGE-1 etc. A number of these human antigens have corresponding non-human mammalian counterparts which share significant homology in their coding sequences and TREs and which may find utility in the practice of the present invention.
Several viruses have recently come forth as both vehicles for gene therapy and as candidate anticancer agents. Among them adenovirus, a mildly pathogenic human virus that propagates prolifically in epithelial cells, the origin of many human cancers. Adenovirus has emerged as a virus that can be engineered with oncotropic properties (see Yu et al. (1999) Cancer Res. 59:1498–1504; Alemany et al. (2000) Nat. Biotechnol. 18:723–727; and Hallenbeck et al. (1999) Hum. Gene Ther. 10:1721–1733). An area that is of interest is the development of replication competent adenovirus vectors designed to selectively replicate in tumor cells. Improving the delivery of these adenoviruses, both to local-regional and disseminated disease, as well as improving the virus to promote intratumoral spread are of particular interest.
Several experimental cancer therapies utilize various aspects of adenovirus or adenovirus vectors. See, for example, U.S. Pat. No. 5,846,945; U.S. Pat No. 5,801,029; PCT/US99/08592; U.S. Pat. No. 5,747,469; PCT/US98/03514; and PCT/US97/22036.
Although replication competent adenoviruses may be able to achieve selective targeting and amplification for the treatment of local and disseminated cancer, there remains a need for improvement in both the adenovirus vectors themselves and methods for their use. Preliminary results suggest that the features of effective treatment strategies for various types of cancer will require development of specific adenovirus vectors and/or methods particular to the type of cancer under treatment. Although chemotherapy and immunotherapy are the most prevalent current therapeutic strategies for disseminated tumors, both toxic side effects and lack of efficacy remain a problem.